Polylactic acid implants (New-Fill) to correct facial lipoatrophy in HIV-infected patients: results of the open-label study VEGA

BACKGROUND: In the absence of currently available therapy to manage facial lipoatrophy, strategies used to compensate for facial fat loss warrant clinical evaluation. METHODS: The goal of this open-label, single-arm, pilot study was to evaluate the efficacy and safety of facial injections of poly-L-lactic acid (PLA) (New-Fill) in HIV-infected patients with severe facial lipoatrophy. Patients received four sets of injection at day 0 and then every 2 weeks for 6 weeks. Patients were evaluated by clinical examination, facial ultrasonography, and photography at screening and at weeks 6, 24, 48, 72, and 96. RESULTS: Fifty patients were enrolled. At entry, the median facial fat thickness was equal to zero (range, 0.0-2.1 mm). The median total cutaneous thickness (TCT) increased significantly from baseline : +5.1 mm (range, 2.2-8.6 mm) at week 6, +6.4 mm (range, 3.1-9.1 mm) at week 24, +7.2 mm (range, 4.2-9.6 mm) at week 48, +7.2 mm (range, 3.5-9.6 mm) at week 72 and +6.8 mm (range, 3.9-10.1 mm) at week 96 (P < 0.001). The proportion of patients with TCT > 10 mm was observed in 19% at week 6, 41% at week 24, 61% at week 48, 52% at week 72 and 43% at week 96. In 22 (44%) patients, palpable but non-visible subcutaneous micronodules were observed with a spontaneous resolution in six patients at week 96. CONCLUSION: The benefit of PLA for the correction of the facial lipoatrophy in HIV-infected patients was clearly demonstrated, with an evident aesthetic and quality of life improvement. The efficacy, safety profile, and the simplicity of the injection schedule of PLA make this filling material a potentially attractive treatment.     

Pancreatic duct stones in chronic pancreatitis: criteria for treatment intensity and success

BACKGROUND: The aim of the study was to evaluate interventional endoscopic management of pancreatic duct stones in patients with chronic pancreatitis by describing therapeutic methods and defining factors that predict technical success. METHODS: Records were retrospectively analyzed for 125 patients with symptoms caused by chronic pancreatitis with pancreatic duct stones (single 43, multiple 82) treated by interventional endoscopy, including extracorporeal shockwave lithotripsy. RESULTS: Technical success was achieved in 85% of patients (11 patients by mechanical lithotripsy, 114 by piezoelectric extracorporeal shockwave lithotripsy). There were no serious complications from lithotripsy. Univariate analysis disclosed a statistically significant association between treatment success and patient age as well as prepapillary location of stones. A greater therapeutic effort was necessary in patients with stones located in the tail of the pancreas, 2 or more stones, a stone 12 mm or more in diameter, or who have had a longer duration (>8 years) of the disease. However, with exception of the last parameter, correction for multiple testing of data removed statistical significance. CONCLUSIONS: Extracorporeal shockwave lithotripsy enhances endoscopic measures for treatment of pancreatic duct stones when mechanical lithotripsy fails. Middle-aged patients in the early stages of chronic pancreatitis with stones in a prepapillary location proved to be the best candidates for successful treatment. Unfavorable patient-related or morphologic factors can be compensated for through more intense efforts at therapy.     

A five-drug remission induction regimen with intensive consolidation for adults with acute lymphoblastic leukemia: cancer and leukemia group B study 8811

The goal of this phase II multicenter clinical trial was to evaluate a new intensive chemotherapy program for adults with untreated acute lymphoblastic leukemia (ALL) and to examine prospectively the impact of clinical and biologic characteristics on the outcome. One hundred ninety-seven eligible and evaluable patients (16 to 80 years of age; median, 32 years of age) received cyclophosphamide, daunorubicin, vincristine, prednisone, and L-asparaginase; 167 patients (85%) achieved a complete remission (CR), 13 (7%) had refractory disease, and 17 (9%) died during induction. A higher CR rate was observed in younger patients (94% for those < 30 years old, 85% for those 30 to 59 years old, and 39% for those > or = 60 years old, P < .001) and in those who had a mediastinal mass (100%) or blasts with a T-cell immunophenotype. Eighty percent of B-lineage and 97% of T-cell ALL patients achieved a CR (P = .01). The coexpression of myeloid antigens did not affect the response rate or duration. Seventy percent of those with cytogenetic or molecular evidence of the Philadelphia (Ph) chromosome and 84% of those without such evidence achieved a CR (P = .11). Patients in remission received multiagent consolidation treatment, central nervous system prophylaxis, late intensification, and maintenance chemotherapy for a total of 24 months. After a median follow-up time of 43 months, the median survival for all 197 patients is 36 months; the median remission duration for the 167 CR patients is 29 months. Favorable pretreatment characteristics relative to remission duration or survival are younger age, the presence of a mediastinal mass or lymphadenopathy, a white blood cell count (WBC) less than 30,000/microL, L1 morphology, T or TMy immunophenotype, and the absence of the Ph chromosome. The estimates of the proportion surviving at 3 years are 69% for patients less than 30 years old, 39% for those 30 to 59 years old, 89% for those who had a mediastinal mass, 59% with WBC less than 30,000/microL, 63% with L1 morphology, 69% for T or TMy antigen expression, and 62% for those who lack the Ph chromosome. Fifteen patients (8%) had no unfavorable prognostic factors and have an estimated probability of survival at 5 years of 100% (95% confidence interval, 77% to 100%). This intensive chemotherapy regimen produces a high remission rate and a high proportion of durable remissions in adults with ALL.     

Quantitative liver function in patients with rheumatoid arthritis treated with low-dose methotrexate: a longitudinal study

The objectives were to determine quantitative liver function prospectively in patients with rheumatoid arthritis (RA) treated with low-dose methotrexate (MTX), to search for risk factors for a loss of quantitative liver function and to assess the relationship between quantitative liver function and histological staging. A total of 117 patients with RA (ACR criteria, 85 women, mean age 59 yr) had measurements of galactose elimination capacity (GEC), aminopyrine breath test (ABT) and liver enzymes [aspartate amino transferase (AST), alanine amino transferase (ALT), alkaline phosphatase (AP), 7-glutamyl transferase (GGT), bile acids, bilirubin, albumin] before treatment with weekly i.m. MTX injections and every year thereafter. In 16 patients, liver biopsies were performed. Before the introduction of MTX, mean GEC was 6.6 mg/min/kg [5th to 95th percentile (5-95 PC) 5.1- 8.5; reference range 6.0-9.1] and mean ABT was 0.80% kg/mmol (5-95 PC 0.42-1.30: reference range 0.6-1.0). During treatment with MTX [mean weekly dose 11.8 mg (5-95 PC 5.4-20.2), mean observation period 3.8 yr (5-95 PC 0.4-6.9)], significant declines of GEC (-0.12 mg/min/kg per year. t = 3.30, P < 0.002) and ABT (-0.06% kg/mmol per year, t = 4.81, P < 0.001) were observed. Negative correlations were found between the annual change in GEC and GEC at baseline (Rs = -0.40, P < 0.0001), and the annual change in ABT and ABT at baseline (Rs = -0.43, P < 0.0001). No correlations were found between the annual change in GEC or ABT and weekly MTX dose, age or percentage of increased liver enzymes, and no effect of a history of alcohol consumption > 30 g/week became evident. Two patients with Roenigk grade III had impaired quantitative liver function, while 14 patients with Roenigk grades I and II exhibited a high variability of GEC and ABT from normal to abnormal values. The continuous declines in GEC and ABT observed deserve attention in patients with prolonged treatment. Patients with a low GEC or ABT at baseline seem not to be at increased risk for a further loss of quantitative liver function. An impaired GEC or ABT does not necessarily concur with hepatic fibrosis on histological examination.      

Identification of components of a phosphoinositide signaling pathway in retinal rod outer segments

Phototransduction in retinal rods involves a G protein-coupled signaling cascade that leads to cGMP hydrolysis and the closure of cGMP-gated cation channels that are open in darkness, producing a membrane hyperpolarization as the light response. For many years there have also been reports of the presence of a phosphoinositide pathway in the rod outer segment, though its functions and the molecular identities of its components are still unclear. Using immunocytochemistry with antibodies against various phosphoinositide-specific phospholipase C (PLC) isozymes (β1–4, γ1–2, and δ1–2), we have found PLCβ4-like immunoreactivity in rod outer segments. Similar experiments with antibodies against the α-subunits of the G_q family of G proteins, which are known to activate PLCβ4, have also demonstrated G_α11-like immunoreactivity in this location. Immunoblots of total proteins from whole retina or partially purified rod outer segments with anti-PLCβ4 and anti-G_α11 antibodies gave, respectively, a single protein band of the expected molecular mass, suggesting specific labelings. The retinal locations of the two proteins were also supported by in situ hybridization experiments on mouse retina with probes specific for the corresponding mouse genes. These two proteins, or immunologically identical isoforms, therefore likely mediate the phosphoinositide signaling pathway in the rod outer segment. At present, G_α11 or a G_α11-like protein represents the only G protein besides transducin (which mediates phototransduction) identified so far in the rod outer segment. Although absent in the outer segment layer, other PLC isoforms as well as G_αq (another G_q family member), are present elsewhere in the retina.     

Cytogenetic and histologic correlations in malignant lymphoma

Although a number of studies have indicated correlations between histologic subtypes of tumors and certain nonrandom chromosome changes, cytogenetic studies of lymphoma are in an early stage compared to those of leukemia. No comprehensive analysis of available data has so far been attempted in the literature either. Here we present an analysis of chromosome changes and their correlation with subtypes of lymphoma studied by conventional histology and cell surface markers, as observed in two sets of data: a group of 65 karyotypically abnormal tumors sequentially ascertained and studied by us during the period January 1, 1984 to April 30, 1985, and a larger data set derived by combining our data with those from two published series from the University of Minnesota that are comparable to our data. These combined data, which comprise the largest data set on the cytogenetics of lymphomas assembled so far, enabled a comprehensive analysis of correlation between chromosome change and tumor histology and the patterns of chromosome instability in these tumors. We found several significant associations, some previously described and others now recognized, between nonrandom chromosome gains, breaks, translocations, and deletions and histologic subtypes of tumors that characterize lymphomas. The data indicate that finding of chromosome breaks at certain sites (eg, 8q24, 14q32, 18q21) is of diagnostic value in dealing with cases of unusual lymphoma. Furthermore, nonrandom chromosome breakage exhibited three distinct patterns that reflected three levels of etiologically relevant genetic change.     

Balloon dilatation of porcine bioprosthetic valves in the pulmonary position

Balloon dilatation (BD) of bioprosthetic valves was investigated in vivo and in vitro. Four children with stenotic bioprosthetic porcine valves in the pulmonary position underwent BD of the valve 10 to 24 months after its insertion. Average valve gradient was reduced from 47.5 to 27 mm Hg. Obstruction at the conduit-branch pulmonary artery connection became apparent after dilatation of the valve. These distal stenoses were also dilated. BD technique was tested in vitro with the use of nonstenotic valves in fresh conduits. No damage to the valve or to the conduit was found when oversized balloons were used in a standard fashion or intentionally inflated until rupture. It is concluded that conduit replacement may be deferred by balloon dilatation of obstructed biological valves and/or a stenotic conduit-pulmonary artery anastomosis.     

B-cell growth factor receptor expression and B-cell growth factor response of leukemic B cell precursors and B lineage lymphoid progenitor cells

The purpose of this study was to analyze the expression of B cell growth factor (BCGF) receptors and to elucidate the biologic effects of biochemically purified natural BCGF at the B cell precursor stage of human B lineage lymphoid differentiation. The specific binding of radioiodinated high-mol-wt BCGF (125I-HMW-BCGF) and low-molecular-wt BCGF (125I-LMW-BCGF) to fresh marrow blasts from B cell precursor acute lymphoblastic leukemia (ALL) patients was initially investigated. The estimated number of radioiodinated BCGF molecules bound per blast ranged from undetectable to 24.3 X 10(3) for HMW-BCGF, and from 11.5 X 10(3) to 457.8 X 10(3) for LMW-BCGF. In 3H-TdR incorporation assays, 75% of cases showed a significant response to LMW-BCGF with a median stimulation index of 9.3. By comparison, only 33% of cases showed a significant response to HMW-BCGF with a median stimulation index of 2.4. Subsequently, B cell precursor colony assays were performed to assess and compare the biologic effects of BCGF on leukemic B lineage lymphoid progenitor cells. Among 28 cases studied, 57% responded to both HMW-BCGF and LMW-BCGF, 21% responded only to LMW-BCGF, and the remaining cases showed no proliferative response to either growth factor. The response patterns of virtually pure populations of FACS- sorted leukemic B cell precursors were essentially identical to the proliferative responses of unsorted leukemic B-cell precursors. Synergistic effects between HMW-BCGF and LMW-BCGF were observed in 80% of the cases that responded to both. The numbers of cell-bound radioiodinated BCGF molecules, the stimulation indices, as well as the number of B cell precursor colonies in BCGF-stimulated cultures showed a marked interpatient variation. Patients with structural chromosomal abnormalities (SCAs) involving 12p11-13 or patients with a Philadelphia chromosome showed a greater HMW-BCGF response at the level of leukemic progenitor cells than did other patients (P = .02). The LMW-BCGF response was significantly greater for patients with SCA than for patients without SCA (P = .04). The response of leukemic progenitor cells to HMW-BCGF or LMW-BCGF did not correlate with sex, age, disease status, FAB morphology, WBC at diagnosis, or immunophenotype. To our knowledge, this study represents the first detailed analyses of BCGF receptor expression and BCGF effects in B cell precursor ALL. The data presented provide direct evidence for the expression of functional receptors for both HMW-BCGF and LMW-BCGF in B cell precursor ALL.     

The clinical evolution of Lyme arthritis

To determine the clinical evolution of Lyme arthritis, 55 patients who did not receive antibiotic therapy for erythema chronicum migrans were followed longitudinally for a mean duration of 6 years. Of the 55 patients, 11 (20%) had no subsequent manifestations of Lyme disease. From 1 day to 8 weeks after disease onset, 10 of the patients (18%) began to have brief episodes of joint, periarticular, or musculoskeletal pain for as long as 6 years, but they never developed objective joint abnormalities. From 4 days to 2 years after disease onset, 28 (51%) had one episode or began to have intermittent attacks of frank arthritis, primarily in large joints; a few had polyarticular movement. The total number of these patients who continued to have recurrences decreased by 10% to 20% each year. The remaining 6 patients (11%) developed chronic synovitis later in the illness; of these, 2 (4%) had erosions, and 1 (2%), permanent joint disability. The spectrum of Lyme arthritis ranges from subjective joint pain, to intermittent attacks of arthritis, to chronic erosive disease.